EP3454906A1 - Taille et distribution des particules d'un polymère pour application de type extrusion par fusion - Google Patents

Taille et distribution des particules d'un polymère pour application de type extrusion par fusion

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Publication number
EP3454906A1
EP3454906A1 EP17727497.4A EP17727497A EP3454906A1 EP 3454906 A1 EP3454906 A1 EP 3454906A1 EP 17727497 A EP17727497 A EP 17727497A EP 3454906 A1 EP3454906 A1 EP 3454906A1
Authority
EP
European Patent Office
Prior art keywords
pva
μιτι
polyvinyl alcohol
particle size
powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17727497.4A
Other languages
German (de)
English (en)
Inventor
Dieter Lubda
Mengyao ZHENG
Nicole DI GALLO
Anja-Nadine KNUETTEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP3454906A1 publication Critical patent/EP3454906A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/022—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the choice of material
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0016—Plasticisers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/005—Stabilisers against oxidation, heat, light, ozone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2029/00—Use of polyvinylalcohols, polyvinylethers, polyvinylaldehydes, polyvinylketones or polyvinylketals or derivatives thereof as moulding material
    • B29K2029/04—PVOH, i.e. polyvinyl alcohol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates to an improved powdered polyvinyl alcohol (PVA), and that due to its improved properties can be better dosed during formulation processes. Furthermore, this invention refers to pharmaceutical formulations comprising polyvinyl alcohol as carrier matrix and their use.
  • PVA powdered polyvinyl alcohol
  • the active ingredient is present as a homogeneous dispersion or solution in carrier.
  • Solid dispersions are defined as being a dispersion of one or more active ingredients in an inert solid matrix and can broadly classified as those containing a drug substance in the crystalline state or in the amorphous state [Chiou W. L, Riegelman S. Pharmaceutical applications of Solid dispersion systems; J. Pharm Sci. 1971 , 60 (9), 1281 - 1301 ].
  • Solid dispersions containing pharmaceutical active ingredients in the crystalline state provide dissolution enhancement by simply decreasing surface tension, reducing agglomeration, and improving wettability of the active substance [Sinswat P., et al.; Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution; Int. J.
  • solid dispersions can be created by a number of methods, including, but not limited to, spray-drying, melt extrusion, and thermokinetic compounding.
  • hot melt extrusion a fusion processing technique
  • HME hot melt extrusion
  • thermoplastic carrier may be mixed with a pharmaceutical active substance and optional inert excipients and further additives.
  • the mixture is fed into rotating screws that convey the powder into a heated zone where shear forces are imparted into the mixture, compounding the materials until a molten mass is achieved.
  • the polymeric carrier vehicle For an amorphous dispersion via melt extrusion, the polymeric carrier vehicle must first possess a thermoplasticity that allows the polymer to be passed through the extruder, and on the other hand the carrier must be thermally stable at barrel temperatures above the glass transition
  • polyvinyl alcohol (PVA) is an excellent compound, which is suitable for (hot) melt extrusion, as carrier for pharmaceutically active ingredients.
  • polyvinyl alcohol (PVA) is a synthetic water-soluble polymer that possesses excellent film-forming, adhesive, and emulsifying properties. It is prepared from polyvinyl acetate, where the functional acetate groups are either partially or completely hydrolyzed to alcohol functional groups.
  • the glass transition temperature varies depending on its degree of hydrolysis. For example, a 38% hydrolyzed material has no melting point, but a glass transition temperature of approximately 48°C, whereas a 75 - 88 % hydrolyzed material has a melting temperature of approximately 190 - 200°C.
  • Polyvinyl alcohol is soluble in water, but almost insoluble in almost all organic solvents, excluding, in some cases, in ethanol. This aspect of the polymer makes it very difficult to form amorphous and solid dispersions through spray drying when the drug has also a limited solubility in aqueous media.
  • US 5,456,923 A provides a process for producing a solid dispersion, which overcomes disadvantages of the conventional production technology for solid dispersions.
  • the process comprises employing a twin-screw extruder in the production of a solid dispersion.
  • a solid dispersion can be expediently produced without heating a drug and a polymer up to or beyond their melting points and without using an organic solvent for dissolving both components and the resulting solid dispersion has excellent performance characteristics.
  • the process claims a polymer that is natural or synthetic and can be employed as a raw material where the polymer's functions are not adversely affected by passage through the twin screw extruder.
  • EP 2 105 130 A1 describes a pharmaceutical formulation comprising a solid dispersion having an active substance embedded in a polymer in
  • Thermoplastic polymers are claimed as drug carriers to form a solid dispersion. It is claimed that the solid dispersion is obtained by melt extrusion. The process comprises melting and mixing the polymer and the active ingredient, cooling, grinding, mixing with the external polymer, and producing a pharmaceutical formulation. It is claimed that the melting is carried out at a temperature below the melting point of the drug.
  • the melting is carried out at a temperature above the T g or melting point of the polymer, but from 0,1 - 5 °C below the melting point of the API.
  • the melting point of pharmaceutical grades of PVA is normally above 178°C, although the glass transition temperature is in the range of 40 - 45 °C.
  • Another object of this invention is to provide improved PVA(s) in a form which allows that the polymer can be melt extruded without addition of significant amounts of additives.
  • extrudable polyvinyl alcohol (PVA) powder shows improved flowability, which is cryo-milled and which has particle sizes in the range of 45 to 1400 ⁇ , preferably in the range of 45 to 1000 ⁇ , most preferred in the range of 50 to 300 ⁇ .
  • PVA showing these properties is hot melt extrudable or melt extrudable.
  • polyvinyl alcohol grades which are showing these properties, are those having viscosities ⁇ 40 mPa.s, whereby the viscosity being measured on 4 % aqueous solution at 20°C (DIN 53015).
  • polyvinyl grades fulfilling said conditions are preferably selected preferably from the group: PVA 3-80, PVA 3-85, PVA 3-88, PVA 3- 98, PVA 4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, P VA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA23-88, PVA 26-80, PVA 26-88, PVA28-99, PVA 30-98, PVA 30-92, PVA 32-88, PVA 40-88, most preferred from the group: PVA 3-88, PVA 4 - 88, PVA 5-74, PVA 5-88, PVA 8-88, and PVA 18-88.
  • a PVA grade is subject matter of the present invention, which is suitable as carrier for the preparation of pharmaceutical formulations and which is a milled pharmaceutical grade powder showing an improved flowability enabling an uninterrupted feeding and dosing during processing.
  • polyvinyl alcohol as described above is homogeneously mixed with at least one active pharmaceutical ingredient, whereby this mixture is storage and transport-stable, and shows an improved flowability which leads to an uninterrupted feeding and dosing during processing.
  • This powdery composition may comprise at least one additive selected from the group plasticizers, surface active materials, antioxidants, stabilizing agents, solubility-enhancing agents, pH control agents and flow regulators.
  • the powdery composition of the present invention is a milled powder comprising polyvinyl alcohol and optionally one or more further excipient(s) with particle sizes in the range of 45 ⁇ to 1400 ⁇ , preferably in the range of 45 to 1000 ⁇ , most preferred in the range of 50 to 300 ⁇ .
  • the present invention also consists in a method for producing the PVA powder according to the invention with improved properties for the manufacture of pharmaceutical formulations, in particular for the production of extruded formulations.
  • Said method or process for producing a solid pharmaceutical dosage form is characterized in that the mixture of ingredients including the powdered polyvinyl alcohol or including the powdery composition as characterized above is processed in an extruder to a homogeneous melt, and that then the feeds are shaped either to a powder or to molded forms.
  • the particular advantage of the present invention is that the process can be carried out continuously, in that the mixture of ingredients including the powdered polyvinyl alcohol having the improved properties is evenly fed into the feeder line of the extruder and that it is processed to a
  • the process according to the present invention includes the steps of
  • pharmaceutical ingredient and optionally with at least one additive selected from the group plasticizer, surface active material, antioxidant, stabilizing agent, solubility-enhancing agents, pH control agents and flow regulators and
  • PVA polyvinyl alcohol
  • PVA polyvinyl alcohol
  • a solid pharmaceutical dosage form which is characterized as disclosed herein and which is obtainable by a process as characterized here, is the subject of the present invention.
  • a homogenous melt, or mixture or form refers to the various compositions that can be made by extruding the made-up source material, which is prepared by milling and combining selected sieve fractions.
  • heterogeneously homogeneous composite refers to a material composition having at least two different materials that are evenly and uniformly distributed throughout the volume and which are prepared of the one or more APIs and the one or more pharmaceutically acceptable excipients, including a pretreated PVA into a composite.
  • bioavailability is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is not highly soluble.
  • pharmaceutically acceptable refers to molecular entities, compositions, materials, excipients, carriers, and the like that do not produce an allergic or similar untoward reaction when
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable materials” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art.
  • the API active pharmaceutical ingredient
  • a "pharmaceutically acceptable salt” is understood to mean a compound formed by the interaction of an acid and a base, the hydrogen atoms of the acid being replaced by the positive ion of the base.
  • solubility As used herein, “poorly soluble” refers to having a solubility means the substance needs > 100 ml solvent to dissolve 1 g substance.
  • dso average particle sizes
  • derivative refers to chemically modified inhibitors or stimulators that still retain the desired effect or property of the original API. Such derivatives may be derived by the addition, removal, or substitution of one or more chemical moieties on the parent molecule. Such moieties may include, but are not limited to, an element such as a hydrogen or a halide, or a molecular group such as a methyl group. Such a derivative may be prepared by any method known to those of skill in the art. The properties of such derivatives may be assayed for their desired properties by any means known to those of skill in the art. As used herein, “analogs" include structural equivalents or mimetics.
  • APIs suitable for use in accordance with the present disclosure can be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the APIs may be used in a variety of application modalities, including oral delivery as tablets, capsules or suspensions; pulmonary and nasal delivery; topical delivery as emulsions, ointments or creams; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depot.
  • parenteral includes subcutaneous, intravenous, intramuscular, or infusion routes of administration.
  • the solution agent used in the solution can be an aqueous such as water, one or more organic solvents, or a combination thereof.
  • the organic solvents can be water miscible or non-water miscible.
  • Suitable organic solvents include but are not limited to ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, tert. -butyl alcohol, dimethyl sulfoxide, ⁇ , ⁇ -dimethyl formamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, toluene, hexanes, heptane, pentane, and combinations thereof.
  • excipients and adjuvants that may be used in the presently disclosed compositions and composites, while potentially having some activity in their own right, for example, antioxidants, are generally defined for this application as compounds that enhance the efficiency and/or efficacy of the effective ingredients. It is also possible to have more than one effective ingredient in a given solution, so that the particles formed contain more than one effective ingredient.
  • excipients and adjuvants may be used to enhance the efficacy and efficiency of the APIs.
  • Thermal binders may also be used in the presently disclosed compositions and composites.
  • the formulations can be designed to be suitable in different release models, which are well known to the skilled person, as there are: immediate, rapid or extended release, delayed release or for controlled release, slow release dosage form or mixed release, including two or more release profiles for one or more active pharmaceutical ingredients, timed release dosage form, targeted release dosage form, pulsatile release dosage form, or other release forms.
  • the resulting composites or compositions disclosed herein may also be formulated to exhibit enhanced dissolution rate of a formulated poorly water soluble drug.
  • the United States Pharmacopeia-National Formulary mandates that an acceptable polyvinyl alcohol for use in pharmaceutical dosage forms must have a percentage of hydrolysis between 85 and 89 %, as well as a degree of polymerization between 500 and 5000.
  • the European Pharmacopoeia mandates that an acceptable polyvinyl alcohol for use in pharmaceutical dosage forms must have an ester value no greater than 280 and a mean relative molecular mass between 20,000 and 150,000.
  • the percentage of hydrolysis (H) can be calculated from the following equation:
  • Powdery compositions according to the invention may comprise at least a biologically active ingredient combined with a PVA that is pharmaceutically acceptable, which is combined with another pharmaceutically acceptable polymer.
  • Such pharmaceutically acceptable polymer can also be selected from the group of hydrophilic polymers and can be a primary or secondary polymeric carrier that can be included in the composition disclosed herein and including polyethylene-polypropylene glycol (e.g. POLOXAMERTM), carbomer, polycarbophil, or chitosan, provided that they are as free-flowing powder and are extrudab!e polymers.
  • Hydrophilic polymers for use with the present invention may also include one or more of hydroxypropyl methylcellulose, ca rboxy m ethy I eel I u lose , hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar, gum acacia, gum tragacanth, or gum xanthan, and povidone. Hydrophilic polymers also include polyethylene oxide, sodium carboxymethylcellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose,
  • polyvinylpyrrolidones polyacrylamides, polymethacrylamides,
  • polyphosphazines polyoxazolidines, poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer, ammonium alginate, sodium alginate, or mixtures thereof.
  • the polymer must be thermoplastic, must have a suitable glass transition temperature and a high thermal stability.
  • the polymer must have no toxic properties and must have a high biocompatibility, etc. Therefore, pharmaceutical grades of polyvinyl alcohol (PVA), which are chosen here for the preparation of formulations comprising active ingredients by hot melt extrusion, are those having a low viscosity.
  • PVA polyvinyl alcohol
  • Polyvinyl alcohol is a synthetic polymer, which is produced by polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer.
  • chemical and physical properties of polyvinyl alcohol such as viscosity, solubility, thermal properties, etc. are very depending on its degree of polymerization, chain length of PVA polymer, and the degree of hydrolysis.
  • PVA can be used for the production of different formulations for various modes of administration to treat a variety of disorders. Accordingly, PVA is processed in a wide range of pharmaceutical dosage forms, including ophthalmic, transdermal, topical, and especially, oral application forms. As mentioned above, it is for the successful industrial processing of a solid in an extrusion process also necessary that a uniform continuous metering is possible in the feed of the extruder.
  • the solid must have suitable particle characteristics, including appropriate particle sizes, and flowability or fluidity.
  • the resulting mixture can be fed continuously without problems and without any halt into the feeder of an extruder.
  • the pretreatment of the applied PVA makes, that the extrusion process is feasible in a simple manner.
  • not only the milling to a fine powder improves the uniform feeding of the PVA powder into the feeder of the extruder.
  • further significant improvement in the flowability of the milled polymer powder is achieved by sieving the milled polymer into various sieve fractions, and subsequent combining certain sieve fractions having specific grain sizes with each other.
  • clearly defined particle sizes and size distributions result in PVA powders with significantly improved flowability and thus in an improved processability of the received PVA powders.
  • PVA solid polyvinyl alcohol
  • PVA polyvinyl alcohol
  • Powders comprising particles larger than in the range of about 1400 ⁇ , cannot be fed into the feeder, because of a lack of homogeneity of the mixture of ingredients and PVA particles, especially because they tend to stick and to agglomerate, but also they tend to separate out, because of the different sized ingredients that segregate.
  • a particularly troublesome problem in this case is that pharmaceutical active ingredients (APIs), which have smaller particle diameters, segregate during feeding, and in the following it is not any more possible to achieve a homogeneous distribution in the carrier polymer during extrusion.
  • APIs pharmaceutical active ingredients
  • compositions always add up to a total of 100 % and not more. Given temperatures are measured in °C.
  • Charge 1 Particle size in the range of ⁇ 45 ⁇ ;
  • Charge 2 Particle size in the range of 45 - 1400 ⁇
  • the milled PVA powder is physically blended with active ingredients in an amount of 20 -60 % by weight, with or without additional plasticizers.
  • the mixture of PVA powder is characterized regarding to the flowability, homogeneity and feasibility of feeding into the extruder feeder.
  • Powders of PVA particles in the C group are not suitable as matrix for melt extrusion due to the blocking of the extruder feeder and because of their inhomogeneity together with applied active ingredients. Powders of PVA particles lower than 45 m are difficult to be loaded into the extruder feeder due to their bad flowability and due to their tendency to aggregate in the feeder.
  • the feeder can also be combined with a computer to control the feeding accuracy of the powder. Therefore, the particle size and distribution is a significant parameter to influence the feasibility and accuracy of extruder feeding. As described above, the milled PVA makes the extrusion process feasible. This means, that the particle size and distribution should be clearly defined with a particle size
  • Particles larger than this area cannot be fed into the feeder, because the homogeneity of the ingredient/PVA mixture is a problem due to the segregation of API. Additionally, it is very difficult to control the feeding rate of the mixture with large PVA particles. On the other side, particle sizes lower than in this range have an issue with flowability and feeder blocking. Therefore, it is necessary to define suitable particle sizes and size distribution of PVA powders for their application as hot melt extrusion excipients, which have the benefits of good flowability, easy loading, good homogeneity with active ingredients etc.
  • Raw Material Poly vinyl alcohol 4-88, excipient EMPROVE® exp Ph Eur, USP, JPE, Article No. 1 .41350, Merck KGaA, Darmstadt, Germany Raw material PVA 4-88 for milling: This PVA types are as coarse - several millimeters in size: too big to load them into the extruder and difficult to formulate a homogenous solid dispersion system with active ingredients together.
  • Mill condition with liquid nitrogen as cold grinding.
  • the desired particle size is produced empirically in particular by varying the grinding temperature, to control the particle size of PVA.
  • the grinding conditions are varied until the desired particle size is obtained.
  • Feeder 1 (Brabender® Mini-Compounder KETSE 12/36 D)
  • Group B PVA 4-88 Particle Size -» 45 ⁇ -1400 ⁇
  • the feeding-rate of excipients powder into the feeder is evaluated with a real feeder of Brabender® Mini-Compounder KETSE 12/36 D)
  • Indomethacin is used here as a representative model substance. Indomethacin is in water a poorly soluble active ingredient [0,937 mg/L, at 25 °C].
  • the applied polymer [polyvinyl alcohol (PVA)] with different particle size and distribution is blended with 30% API (indomethacin) powder. Real concentration of indomethacin from different positions of the mixture is detected by NMR spectroscopy.
  • the phase and the baseline is corrected for the obtained spectrum.
  • the resonance of the CH protons of maleic acid (ca. 6,3 ppm) and the CH protons of Indomethacin (e.g. 6,7 ppm, 6,9 ppm or 7,0 ppm) are integrated.
  • the integral of maleic acid is set to 100.
  • the content is calculated according to the general formula: zstM x I x m st
  • Mx molar mass of the compound of interest x
  • nrix weighted mass of the compound of interest x
  • Fig. 1 shows a NMR spectrogram of 20 mg indomethacin and 20 mg maleic acid in DMSO-d6
  • a milled PVA powder of PVA 4-88 having this particle size distribution is characterized by the logarithmic plot of particle sizes ranging up to 100 microns to their volume percentage.
  • Fig. 3 shows the differences in the angles of repose of PVA powders of Groups A, B and C without the addition of any API
  • Fig. 4a shows the feeding performance of PVA powder of Group A without
  • the feeding is not uniform and shows irregularities.
  • Fig. 4b shows the feeding performance of PVA powder of Group A with 30
  • the feeding is not uniform and shows comparable irregularities as the feeding of the pure powder.
  • Fig. 4c shows the feeding performance of PVA powder of Group B without
  • the feeding is very uniform.
  • Fig. 4d shows the feeding performance of PVA powder of Group B with 30 % by weight of API. The feeding is also very uniform and is comparable to the feeding of the pure powder of Group B.
  • the best cryo-milled PVA powders show the following particle size distribution:
  • Fig. 5 shows the volume - particle size plot of PVA 4-88, having the
  • the experiments show the relationship of the particle size distribution of PVA in relation to the flow properties as well as in relation to its suitability for its dosage into the feeder of an extrusion plant for hot melt extrusion.
  • PVA powders having suitable particle sizes and size distributions can be used very well for hot melt extrusion excipients thanks to improved flow properties, their easy-to- load and good homogeneity with APIs and so on.
  • PVA powders according to the present invention which have in aqueous solution a viscosity * ⁇ 40 mPa.s, show the advantage to be (hot) melt extrudable by themselves without the addition of any processing aids like additional plasticizer or other active ingredients ( * viscosity is measured as 4,0 % water solution at 20°C DIN 53015).
  • PVA powders which have in aqueous solution a viscosity * > 40 mPa.s, need additional plasticizer or active ingredients as plasticizer to make the mixture extrudable.

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  • Extrusion Moulding Of Plastics Or The Like (AREA)

Abstract

La présente invention concerne un alcool polyvinylique (PVA) en poudre amélioré, qui peut être utilisé pour des produits pharmaceutiques, et qui, en raison de ses propriétés améliorées, peut être mieux dosé pendant le processus de formulation. En outre, cette invention concerne des compositions pharmaceutiques comprenant de l'alcool polyvinylique en tant que matrice de support et leur utilisation.
EP17727497.4A 2016-05-13 2017-05-10 Taille et distribution des particules d'un polymère pour application de type extrusion par fusion Pending EP3454906A1 (fr)

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EP16169690 2016-05-13
PCT/EP2017/061130 WO2017194578A1 (fr) 2016-05-13 2017-05-10 Taille et distribution des particules d'un polymère pour application de type extrusion par fusion

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JP (1) JP7082067B2 (fr)
KR (3) KR20230151062A (fr)
CN (1) CN109069652B (fr)
BR (1) BR112018071740A2 (fr)
CA (1) CA3023801A1 (fr)
IL (1) IL262913A (fr)
MX (1) MX2018013000A (fr)
PH (1) PH12018502103A1 (fr)
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CN112559417B (zh) * 2020-12-09 2023-04-25 广东美的暖通设备有限公司 空调通信的控制方法、装置、通信系统和可读存储介质

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WO2017194578A1 (fr) 2017-11-16
CN109069652B (zh) 2023-03-24
US11246935B2 (en) 2022-02-15
PH12018502103A1 (en) 2019-07-15
BR112018071740A2 (pt) 2019-02-19
CA3023801A1 (fr) 2017-11-16
SG11201809962SA (en) 2018-12-28
IL262913A (en) 2018-12-31
KR20230151062A (ko) 2023-10-31
JP2019520325A (ja) 2019-07-18
CN109069652A (zh) 2018-12-21
US20190111138A1 (en) 2019-04-18
KR20190008334A (ko) 2019-01-23
MX2018013000A (es) 2019-01-28
JP7082067B2 (ja) 2022-06-07
KR20210145306A (ko) 2021-12-01

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